Atopic dermatitis is a pruritic, chronically recurrent inflammatory dermatosis, which has a genetic background and characteristically accompanies high IgE level in the serum. In addition, mast cells and eosinophils gather in the lesion, and eosinophils in the blood also increase. While the mechanism of the onset of atopic dermatitis has not been completely elucidated, activation of basophils and mast cells induced by crosslinking of immunoglobulin (hereinafter to be indicated as Ig) E molecules bound to FcεR on activated T cells, basophils or mast cells, which results in the production of Th2-related cytokine and chemical mediator, is considered to be important. The above-mentioned cytokine refers to interleukin (hereinafter to be indicated as IL)-4, IL-13 and IL-5, and the chemical mediator refers to histamine, serotonin and the like. In this case, antigen specific IgE plays an important role particularly in the activation of basophils and mast cells; however, this does not apply to innate atopic dermatitis for which antigen specificity is not clear and the detail is unknown, though involvement of external stimulation and infection, IL-18 and the like is suggested.
As genetically-engineered atopic dermatitis model mice, 7 lineages [IL-4 Tg, CASP1 Tg, IL-18 Tg, IL-31 Tg, Re1B-KO, CatE-KO (non-patent document 1), MAIL-KO (non-patent document 2)] have been reported.
However, atopic dermatitis model mouse generated by genetic engineering does not necessarily reflect the actual features of atopic dermatitis. For example, some of the models reported as atopic dermatitis models generated by genetic engineering are models (CASP1 Tg, IL-18 Tg, IL-4 Tg) showing enhanced expression of genes; however, they show localization of high expression of genes generally absent in the skin of atopic dermatitis patients, or eosinophil and neutrophil are not found in dermatitis tissues and numerical values of IgE do not show variation (IL-31 Tg), and the like. Therefore, it is considered that they are not necessarily disease models appropriately reflecting atopic dermatitis in human. In addition, Re1B-KO mouse showing no pruritus symptoms and MAIL(IkBζ)-KO mouse showing very high perinatal mortality rate and severe dermatitis symptoms and the like are imperfect as atopic dermatitis models. As such, when these model mice are used for the evaluation of atopic dermatitis, they are feared to reflect non-actual conditions.
In recent years, study of atopic dermatitis has progressed and new findings have been reported. Recently, an increase in the expression of IL-33 in the nucleus of epidermal keratinocytes of the skin of atopic dermatitis patients has been reported (non-patent document 3). IL-33 has been identified as a cytokine belonging to the IL-1 family having an amino acid sequence with high homology with IL-1βand IL-18, and ST2 is the receptor thereof. Since ST2 is expressed on Th2 cells and cells involved in allergy (basophils, mast cells, eosinophils, type 2 innate lymphoid cells), IL-33 suggested to be involved in Th2 type allergic diseases. However, a report indicates that when mouse recombinant IL-33 is directly administered topically into the skin dermis, a scleroderma-like reaction accompanying an increase in the collagenous fibers of dermis occurs, and changes of epidermis do not accompany (non-patent document 4); another report indicates that psoriasis-like dermatitis accompanying epidermis thickening occurs (non-patent document 5). Therefore, an influence of IL-33 on the skin has not been clear. In such situation, a transgenic animal highly expressing IL-33 in the skin has not been found to date, and the phenotype thereof is also unknown.